The invention relates to the use of photodynamic therapy for the destruction of diseased synovium.
Photodynamic therapy generally refers to an experimental cancer treatment modality that selectively kills cancer cells by an interaction between absorbed light an a retained photoactivatable agent (Kessel, Photochem. Photobiol. 44:489-493; Bottiroli et al., Photochem. Photobiol. 47:209-214, 1988; Salet et al., Photochem. Photobiol. 53:391-3, 1991; Gross, Photobiological Techniques (chapter 9), Valenzeno et al. eds., Plenum Press, New York, 1991; Star et al., Photochem and Photobiol, B: Biology 1:149-167, 1987; and Jori et al., Photodynamic Therapy of Neoplastic Disease, Kessel ed., CRC Press, Boca Raton, Fla., 1989). Chemical sensitization of live tissues by light was first reported in 1900 by Raab. Uptake of hematoporphyrin derivative (HPD) in neoplastic tissue was first described by Auler and Banzer (Z. Krebforsch 53:65-68, 1942). Uptake was later confirmed by fluorescence by Figge et al (Proc. Soc. Exp. Biol. Med. 68:640-641, 1948). Lipson et al. demonstrated tumor localization of HPD in 1960 (JNCI 26:1-12, 1961).
The HPD semipurified mixture of porphyrins was later further purified to a combination of esters and ethers of dihematoporphyrin (DHE). The formulation predominantly in use is marketed as Photofrin.RTM. and HPD/Photofrin.RTM. was the first FDA approved photosensitizing agent available for PDT trials. Photofrin.RTM. has subsequently been tested extensively for the destruction of multiple tumors in numerous medical disciplines (Dougherty et al., In Photodynamic Therapy of Neoplastic Disease, Kessel ed., CRC Press, Boca Raton, Fla., 1989).
The mechanism of action for hematoporphyrin derivatives such as Photofrin.RTM. in the treatment of neoplastic disease is well delineated. For the porphyrins, large molecular aggregates accumulate around tumor neovasculature. Poor lymphatic drainage of neoplastic tissues may be the cause of retarded clearance times from these tissues. Once sequestered, the molecular aggregates dissociate, and the hydrophobic components partition Photofrin.RTM. into cell membranes. The primary cellular sites of photodynamic activity are thought to be cellular and mitochondrial membranes. Nucleic acids and proteins are also damaged by photooxidation (Henderson et al., Porphyrin Localization and Treatment of Tumors, Doiron and Gomer eds., Liss, New York, 1984, pp. 601-612).
Initiation of photodynamic activity is caused by excitation of the sensitizer by light that falls within its absorption band. The wavelength specificity is dependent on the molecular structure of the photosensitizer, where a greater degree of conjugation within a molecule leads to greater absorbance at longer wavelengths. Activation of photosensitizers occurs with sub-ablative light fluences. Toxicity is achieved by O.sub.2 radical toxicity. The singlet O.sub.2 reacts with double bonds, and organoperoxides. These, in turn, initiate free radical chain reactions which degrade and disorganize membranes, uncouple oxidative phosphorylation and lead to cellular disruption (Jori et al., Photodynamic Therapy Of Neoplastic Disease, Kessel ed., CRC Press, Boca Raton, Fla., 1989; and Weishaupt et al., Cancer Res 36:2326-2329, 1976).
Several characteristics of photodynamic therapy allow for the selective destruction of diseased tissue without damage to non-pathological tissue (Kessel, Photochem. Photobiol. 44:489-493; Bottiroli et al., Photochem. Photobiol. 47:209-214, 1988; Salet et al., Photochem. Photobiol. 53:391-3, 1991; Gross, Photobiological Techniques (chapter 9), Valenzeno et al. eds., Plenum Press, New York, 1991; Star et al., Photochem and Photobiol, B: Biology 1:149-167, 1987; Jori et al., Photodynamic Therapy of Neoplastic Disease, Kessel ed., CRC Press, Boca Raton, Fla., 1989; Dougherty et al., In Photodynamic Therapy of Neoplastic Disease, Kessel ed., CRC Press, Boca Raton, Fla., 1989; Richelli et al., J. Photochem Photobiol 6:69-77, 1990; and Jori and Spikes, J. Photochem Photobiol. 6:93-101, 1990; Mazierre et al., J. Photochem Photobiol. 6:61-68, 1990; Brault, J. Photochem and Photobiol 6:79-86, 1990; and Pottier, J. Photochem Photobiol. 6:103-109, 1990). Photosensitizing agents are non-toxic until activated by specific frequencies and dosages of light energy. In addition, photosensitizers may be activated when transient differences in uptake occur between pathological and normal tissues. Differences in both temporal and geographic biodistribution in tissues may be taken advantage of for selective destruction of pathological tissue.
Carson, U.S. Pat. No. 5,028,594 describes a method for the selective elimination of hematopoietic cells involved in rheumatoid arthritis by use of photactivatable cytotoxic agents in combination with light. The photoactivated agents are tagged with ligands such as sugars, which target lymphocyte cells. In the example, monoethylenediamine monamide was administered to rats in combination with light, bringing about a reduction in joint swelling and inflammation.
Kennedy, U.S. Pat. No. 5,079,262 describes a method of detecting and treating tissue abnormalities such as skin lesions and tumors by the administration of aminolevulinic acid in combination with photoactivating light. Kennedy suggests the use of ALA, a metabolic precursor of protoporphyrin IX in a variety of PDT applications.
Attempts at destroying diseased synovium with non-selective toxic compounds have been unsuccessful (Goldberg et al, Arthritis Rheum. 19:737, 1976; Mitchell et al., JBJS 55-B:814, 1973; and Oka et al., Acta Rheum Scand 15:35, 1969). Most recently, in an effort to develop minimally invasive techniques, synovectomies have been performed with radioactive compounds (Zuckerman et al., J. Orthop Res. 7:50-60, 1989 and Sledge et al., Clin Orthop Rel Res 182:37-40, 1984). Although success has been achieved to a small degree, the use of radioactivity precludes widespread use.